Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/20—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates, as new products, to pyridazine derivatives.
• It also relates to a process for the preparation of these compounds and to the medicaments which contain, as active principle, at least one of said derivatives.
• the compounds (1) are capable of giving, with mineral or organic acids, addition salts.
• the present invention also relates to the addition salts which the compounds (I) provide with the pharmaceutically acceptable acids.
• the compounds according to the invention can be obtained from 3-chloro pyridazines suitably substituted 1 according to the following reaction scheme:
• the compounds (I) where R 4 is -COOH are obtained from compounds wherein R 4 is -COO-alkyl in Ci-C 4 by acidic saponification, preferably by heating with a hydrogen halide, such as hydrochloric acid or hydrobromic acid, within acetic acid at a temperature between 20 and 100 ° C.
• a hydrogen halide such as hydrochloric acid or hydrobromic acid
• the acid is isolated directly in the form of the salt corresponding to the hydracid used, by evaporation to dryness.
• the compounds (I) where R 4 represents a carboxamido group can be prepared either from the corresponding esters (I) by the action of ammonia in solution in an aliphatic alcohol, such as methanol, or from nitriles (I).
• the acids (I) are obtained by carbonation of the pyridazine substituted in position 3 by a group -NH-Alk where Alk is a 1,2-propynyl group.
• the invention also relates to the pyridazine derivatives obtained by the process which consists in reacting the 3-amino pyridazine of formula 3 with an X-Alk halide in which Alk is a 1,2-propynyl group and subjecting the product obtained to carbonation.
• the 3-chloro pyridazines used as starting materials are known compounds or can be prepared according to known methods and in particular by the action of excess phosphorus oxychloride on the corresponding 2H pyridazones-3.
• the solid is dried at 70 ° C under vacuum to obtain 2 g of the expected product. M> 260 ° C.
• 4-methylphenyl-6 (2-propyne-ylamino) -3 pyridazine is prepared by heating at 60 ° C. for 2 hours from 7 g of 3-amino-4-methylphenyl-6 pyrylazine and 9 ml of propargyl bromide. After evaporation of the excess propargyl bromide, the residue is taken up in 300 ml of anhydrous benzene and 1.77 g of sodium are added. The mixture is brought to reflux for 15 hours, then the solution is poured onto excess dry ice and left in contact for several hours.
• the products according to the invention have been studied with regard to their activity on the central nervous system. Activity on the displacement of 1-aminobutyric acid from its postsynaptic receptor.
• the neurochemical activity of the derivatives of the present invention on the GABA-ergic system was evaluated by measuring the displacement of ⁇ -aminobutyric acid (GABA) from its postsynaptic receptor.
• GABA ⁇ -aminobutyric acid
• the displacement experiment was carried out in vitro in the presence of a suspension of synaptic membranes and of tritiated GABA at the final concentration of 3.6 nM.
• the products of the invention have the ability to displace GABA from its synaptic receptor.
• the tranquilizer-sedative activity of the derivatives of the present invention was evaluated by measuring the spontaneous motility of mice using the actimetry test (JR BOISSIER and P. SIMON, Arch Int Pharmacocyn, 1965, 158, 212-221) .
• mice were placed individually in the cages 45 minutes after the administration of the product orally: each crossing of a light beam was counted by an individual counter. The scores corresponding to the movements of the animals were recorded for 10 minutes. The batches consisted of 12 mice per dose.
• the antidepressant activity of the compounds was evaluated in the test of the antagonism of ptosis to reserpine in mice.
• mice Charles River CD1 female mice, weighing 20 to 24 g, were previously subjected to a unilateral lesion of the striatum by stereotaxic injection of 6- (OH) dopamine at a rate of 8 ⁇ g per animal.
• the product to be studied was administered intraperitoneally to groups of 7 mice. The number of rotations was evaluated for 2 minutes, 1 hour after the administration of the product. Rotations ipsilateral to the lesion were counted positively, those contralateral were counted negatively.
• the algebraic sum of rotations for a group of treated animals was compared with that of the group of control animals having received only the vehicle (physiological saline).
• the tests thus carried out show that the products according to the invention act on the neuron by occupying the receptor site for ⁇ -aminobutyric acid. They have pharmacological properties in animals which can lead them to be used in human therapy for the treatment of mental neurological or neuro-muscular conditions.
• the products according to the invention can be used for mood or behavioral disorders such as depressive states, asthenia, Parkinson's disease, eating disorders or insomnia.
• compositions can be solid or liquid and can be presented, for example, in the form of tablets, capsules, granules, suppositories or injectable preparations.
• the dosage can vary within wide limits, in particular according to the type and severity of the condition to be treated and according to the method of administration. Most often in adults orally, it is between 0.050 and 0.500 g per day, possibly divided into several doses.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Neurosurgery (AREA)
• Life Sciences & Earth Sciences (AREA)
• Neurology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Biomedical Technology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Anesthesiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 1983
  • 1983-01-27 FR FR8301234A patent/FR2540113A1/fr active Granted
• 1984
  • 1984-01-18 CA CA000445481A patent/CA1238637A/en not_active Expired
  • 1984-01-20 PH PH30135A patent/PH21162A/en unknown
  • 1984-01-20 AR AR295532A patent/AR240045A1/es active
  • 1984-01-23 IL IL70756A patent/IL70756A/xx unknown
  • 1984-01-23 ZA ZA84502A patent/ZA84502B/xx unknown
  • 1984-01-23 PT PT77993A patent/PT77993B/pt not_active IP Right Cessation
  • 1984-01-23 IE IE149/84A patent/IE57054B1/en not_active IP Right Cessation
  • 1984-01-23 ES ES529081A patent/ES529081A0/es active Granted
  • 1984-01-24 AU AU23729/84A patent/AU2372984A/en not_active Abandoned
  • 1984-01-25 EP EP84400156A patent/EP0117779B1/fr not_active Expired
  • 1984-01-25 AT AT84400156T patent/ATE48417T1/de not_active IP Right Cessation
  • 1984-01-25 DE DE8484400156T patent/DE3480653D1/de not_active Expired - Fee Related
  • 1984-01-26 KR KR1019840000335A patent/KR910000638B1/ko not_active IP Right Cessation
  • 1984-01-26 MA MA20239A patent/MA20018A1/fr unknown
  • 1984-01-26 FI FI840323A patent/FI78691C/fi not_active IP Right Cessation
  • 1984-01-26 OA OA58216A patent/OA07644A/xx unknown
  • 1984-01-26 HU HU84331A patent/HU193890B/hu not_active IP Right Cessation
  • 1984-01-26 NZ NZ206945A patent/NZ206945A/en unknown
  • 1984-01-26 NO NO840313A patent/NO840313L/no unknown
  • 1984-01-26 DD DD84259650A patent/DD220026A5/de not_active IP Right Cessation
  • 1984-01-27 DK DK038984A patent/DK162985C/da active
  • 1984-01-27 YU YU00142/84A patent/YU14284A/xx unknown
  • 1984-01-27 JP JP59013234A patent/JPS59141564A/ja active Pending
  • 1984-01-27 PL PL1984245931A patent/PL142340B1/pl unknown
• 1985
  • 1985-10-03 US US06/783,686 patent/US4721711A/en not_active Expired - Fee Related
• 1988
  • 1988-08-18 AU AU21421/88A patent/AU652118B2/en not_active Ceased
• 1990
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